General Information

Predisposition to Neuroblastoma
Presentation of Neuroblastoma
        Opsoclonus/myoclonus syndrome
Diagnosis
Prognosis
        Age
        Biologic factors
Unique Aspects of Neuroblastoma
        Biologically discrete types of neuroblastoma
        Neuroblastoma screening
        Spontaneous regression of neuroblastoma

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will enable them to achieve optimal survival and quality of life. (Refer to the PDQ summaries on Supportive and Palliative Care for specific information about supportive care for children and adolescents with cancer).

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For neuroblastoma, the 5-year survival rate in the United States has remained stable at approximately 87% for children younger than 1 year and has increased from 37% to 65% in children aged 1 to 14 years.[1] Childhood and adolescent cancer survivors require close follow-up since cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors).

Neuroblastoma is predominantly a tumor of early childhood, with two-thirds of the cases presenting in children aged 5 years or younger. Neuroblastoma originates in the adrenal medulla or the paraspinal sites where sympathetic nervous system tissue is present. These tumors can be divided into low-, intermediate-, and high-risk groups as illustrated in the Stage Information section of this summary. Low- and intermediate-risk patients usually have localized disease or are infants aged 18 months or younger. In rare cases, neuroblastoma can be discovered prenatally by fetal ultrasonography.[3]

Little is known about the events that predispose to the development of neuroblastoma. Parental exposures have not been definitively linked. In a genome-wide association study of 1,032 patients with neuroblastoma, a significant association was observed between a common genetic variation (polymorphism) at chromosome 6p22 and neuroblastoma. Tumors that arose in patients with this polymorphism tended to be clinically aggressive.[4] Genome-wide association studies in children with neuroblastoma have found a few gene polymorphisms associated with the development of high-risk neuroblastoma and a few other gene polymorphisms associated with the development of low-risk neuroblastoma.[4,5] Germline deletion at the 1p36 or 11q14-23 locus are associated with the development of neuroblastoma and the same deletions are found somatically in sporadic neuroblastomas.[6,7]

About 1% to 2% of patients with neuroblastoma have a family history of neuroblastoma, and these children are on average younger (9 months); about 20% have multifocal primary neuroblastomas. The primary cause of familial neuroblastoma is germline mutation in the ALK gene.[8] Similar somatic mutations and amplification of the ALK gene are found in 8% to12% of sporadic neuroblastomas. The mutations result in constitutive phosphorylation of ALK, which is critical for cell growth of the ALK-mutant neuroblasts. Thus, inhibition of ALK kinase is a potential target for treatment of neuroblastoma, especially in children whose tumors harbor an ALK mutation or ALK gene amplification.[9] Familial neuroblastoma is rarely associated with Ondine’s curse (congenital central hypoventilation syndrome) with germline mutation of the PHOX2B gene.[10]

The most common presentation of neuroblastoma is an abdominal mass. The most common symptoms in high-risk patients are due to a tumor mass or to bone pain from metastases. Proptosis and periorbital ecchymosis are common in these high-risk patients and arise from retrobulbar metastasis. Extensive bone marrow metastasis may result in pancytopenia. Abdominal distention with respiratory compromise due to massive liver metastases may occur in infants. Because they originate in paraspinal ganglia, neuroblastomas may invade through neural foramina and compress the spinal cord extradurally, causing paralysis. Horner syndrome may be caused by neuroblastoma in the stellate ganglion, and children with Horner syndrome without apparent cause should be examined for neuroblastoma and other tumors.[11] Fever, anemia, and hypertension are occasionally found. Multifocal (multiple primaries) neuroblastoma occurs rarely, usually in infants, and generally has a good prognosis.[12] On rare occasions, children may have severe, watery diarrhea due to the secretion of vasoactive intestinal peptide by the tumor, or may have protein-losing enteropathy with intestinal lymphangiectasia.[13] Vasoactive intestinal peptide secretion may also occur upon chemotherapeutic treatment, and tumor resection reduces vasoactive intestinal peptide secretion.[14]

Children with neuroblastoma rarely present with paraneoplastic neurologic findings, including cerebellar ataxia or opsoclonus/myoclonus.[15] Neurologic dysfunction is most often a presenting symptom but may arise long after removal of the tumor. Opsoclonus/myoclonus syndrome is frequently associated with pervasive and permanent neurologic and cognitive deficits, including psychomotor retardation.[16-18]

The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully defined.[16,19] Unlike most other neuroblastomas, the primary tumor is typically diffusely infiltrated with lymphocytes.[20] Patients who present with this syndrome often have neuroblastomas with favorable biological features and are likely to survive, though tumor-related deaths have been reported.[16]

Some patients may clinically respond to removal of the neuroblastoma, but improvement may be slow and partial; symptomatic treatment is often necessary. Adrenocorticotropic hormone treatment is thought to be effective, but some patients do not respond to adrenocorticotropic hormone.[17,19] Various drugs, plasmapheresis, intravenous gamma globulin, and rituximab have been reported to be effective in selected cases.[17,21-23] The long-term neurologic outcome may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects.[15,21] The use of immunosuppressive therapy with and without intravenous gamma globulin in the treatment of patients with neuroblastoma and opsoclonus/myoclonus syndrome is under study by the Children's Oncology Group (COG) (COG-ANBL00P3).

The diagnosis of neuroblastoma requires the involvement of pathologists who are familiar with childhood tumors. Some neuroblastomas cannot be differentiated, via conventional light microscopy, from other small round blue cell tumors of childhood, such as lymphomas, primitive neuroectodermal tumors, and rhabdomyosarcomas. Evidence for sympathetic neuronal differentiation may be demonstrated by immunohistochemistry, electron microscopy, or by finding elevated levels of serum catecholamines (e.g., dopamine and norepinephrine) or urine catecholamine metabolites, such as vanillylmandelic acid (VMA) or homovanillic acid (HVA). The minimum criterion for a diagnosis of neuroblastoma, as has been established by international agreement, is that it must be based on one of the following:

1. An unequivocal pathologic diagnosis made from tumor tissue by light microscopy (with or without immunohistology, electron microscopy, or increased levels of serum catecholamines or urinary catecholamine metabolites).[24]

2. The combination of bone marrow aspirate or trephine biopsy containing unequivocal tumor cells (e.g., syncytia or immunocytologically-positive clumps of cells) and increased levels of serum catecholamines or urinary catecholamine metabolites, as described above.[24]

However, primary tumor tissue is often needed to obtain all the biological data that may be used to determine treatment in current COG clinical trials. There is an absolute requirement for tissue biopsy to determine the International Neuroblastoma Pathology Classification (INPC) (see Cellular Classification section for more information). The INPC was used to determine treatment in the COG risk assignment schema for prior COG studies in patients with stage 2, 3, and 4S tumors. In the risk/treatment group assignment schema for the current COG studies, INPC is used to determine treatment for stage 3 and 4S patients as well as for stage 4 patients aged 18 months or younger. Additionally, a significant number of tumor cells are needed to determine MYCN copy number DNA index and 11q and 1p loss of heterozygosity. For older stage 4 patients, bone marrow with extensive tumor involvement combined with elevated catecholamine metabolites is adequate for study entry.

Approximately 70% of patients with neuroblastoma have metastatic disease at diagnosis. The prognosis for patients with neuroblastoma is related to their age at diagnosis, clinical stage of disease, site of the primary tumor, tumor histology, and, in patients older than 1 year, regional lymph node involvement. Biological prognostic variables are also used to help determine treatment (see below).[25-28] The 5-year overall survival for all infants and children with neuroblastoma has increased from 46% when diagnosed between 1974 and 1989, to 71% when diagnosed between 1999 and 2005;[29] however, this single number can be misleading due to the extremely heterogeneous prognosis based on the neuroblastoma patient's age, stage, and biology. (Refer to the Cellular Classification section of this summary for more information.)

The effect of age at diagnosis on 5-year survival is profound—age younger than 1 year is associated with 90% survival, 1 to 4 years is 68%, 5 to 9 years is 52%, and 10 to 14 years is 66%.[29] Children of any age with localized neuroblastoma and infants aged 18 months and younger with advanced disease and favorable disease characteristics have a high likelihood of long-term, disease-free survival.[30] The prognosis of fetal and neonatal neuroblastoma are similar to that of older infants with neuroblastoma and similar biological features.[31] Older children with advanced-stage disease, however, have a significantly decreased chance for cure, despite intensive therapy. For children aged 18 months and older with stage 4 neuroblastoma, who receive aggressive treatment with surgery and radiation therapy to the primary tumor mass, as well as aggressive chemotherapy with hematopoietic stem cell rescue followed by cis-retinoic acid, long-term survival is approximately 30% to 50%.[32]

The clinical characteristics of neuroblastoma in adolescents are similar to those observed in children. The only exception is that bone marrow involvement occurs less frequently, and there is a greater frequency of metastases in unusual sites such as lung or brain.[33] Neuroblastoma has a worse long-term prognosis in an adolescent or adult compared to a child, regardless of stage or site and, in many cases, a more prolonged course when treated with standard doses of chemotherapy. Aggressive chemotherapy and surgery have been shown to achieve a minimal disease state in more than 50% of these patients.[33-35] Other modalities, such as local radiation therapy and the use of agents with confirmed activity, may improve the poor prognosis.[34,35] However, the overall prognosis for older patients is dismal.

A number of biologic variables have been studied in children with this tumor.[36] Treatment decisions are usually based on important factors such as the INPC (refer to the Cellular Classification section of this summary for information about the INPC system), ploidy, amplification of the MYCN oncogene within tumor tissue, unbalanced 11q loss of heterozygosity, and loss of heterozygosity for chromosome 1p.[28,37-43] In the future, MYCN amplification, 11q23 alleles, and ploidy (along with standardized procedures for evaluation) are expected to be the standard factors used for evaluation of treatment programs, as established by the International Consensus for Neuroblastoma Molecular Diagnostics.[44] An open biopsy is often needed to obtain adequate tissue for determination of these biological characteristics.

Many biological characteristics of tumors are not currently used in determining therapy; however, as clinical research matures, these characteristics may be found useful as therapeutic targets or as clinically important prognostic factors. Amplification of the MYCN gene is associated not only with deletion of chromosome 1p, but also gain of the long arm of chromosome 17 (17q), the latter of which independently predicts a poor prognosis.[45] In contrast to MYCN gene amplification, the degree of expression of the MYCN gene in the tumor does not predict prognosis.[46] However, high overall MYCN-dependent gene expression and low expression of sympathetic neuron late differentiation genes both predict a poor outcome of neuroblastomas otherwise considered to be at low or intermediate risk of recurrence.[47] ATRX is involved in epigenetic gene silencing and telomere length. ATRX mutation without MYCN amplification is associated with age at diagnosis in adolescents and young adults with metastatic neuroblastoma.[48]

Other biological prognostic factors that have been extensively investigated include tumor cell telomere length, telomerase activity, and telomerase ribonucleic acid;[49,50] urinary VMA, HVA, and their ratio;[51] dopamine; CD44 expression; TrkA gene expression; and serum neuron-specific enolase level, serum lactic dehydrogenase level, and serum ferritin level.[36] High-level expression of the MRP1 drug resistance gene is an independent indicator of decreased survival.[52] The profile of GABAergic receptors expressed in neuroblastoma is predictive of prognosis regardless of age, stage, and MYCN gene amplification.[53] Gene expression profiling may prove useful for prognosis prediction.[54] Whole chromosome copy number changes do not predict recurrence, while segmental chromosome number changes do.[55,56] In addition, response to treatment has been associated with outcome. The persistence of neuroblastoma cells in bone marrow during or after chemotherapy, for example, is associated with a poor prognosis.[57,58]

Based on biologic factors and an improved understanding of the molecular development of the neural crest cells that give rise to neuroblastoma, the tumors have been categorized into three biological types. These types are not used to determine treatment at this time; however, type 1 has a very favorable prognosis, while types 2 and 3 have poor prognoses.

• Type 1: Expresses the TrkA neurotrophin receptor, is hyperdiploid, and tends to spontaneously regress.[59,60]

• Type 2: Expresses the TrkB neurotrophin receptor and its ligand, has gained an additional copy of chromosome 17q, has loss of heterozygosity of 14q or 11q, and is genomically unstable.[59,60]

• Type 3: Has a gain of chromosome 17q, loss of chromosome 1p, and the MYCN gene becomes amplified.[59,60]

Children whose tumors have lost a copy of 11q are older at diagnosis, and their tumors contain more segmental changes in gene copy number compared with children whose tumors show MYCN amplification.[61,62] Moreover, segmental chromosome changes not detected at diagnosis may be found in neuroblastomas at relapse. This suggests that clinically important tumor progression is associated with accumulation of segmental chromosomal alterations.[63]

Current data do not support neuroblastoma screening. Screening infants for neuroblastoma by assay of urinary catecholamine metabolites was initiated in Japan.[64] A large population-based North American study, in which most infants in Quebec were screened at the ages of 3 weeks and 6 months, has shown that screening detects many neuroblastomas with favorable characteristics [65,66] that would never have been detected clinically, apparently due to spontaneous regression of the tumors. Another study of infants screened at the age of 1 year shows similar results.[67] Screening at the ages of 3 weeks, 6 months, or 1 year caused no reduction in the incidence of advanced-stage neuroblastoma with unfavorable biological characteristics in older children, nor did it reduce the number of deaths from neuroblastoma in infants screened at any age.[66,67] No public health benefits have been shown from screening infants for neuroblastoma at these ages. (Refer to the PDQ summary Neuroblastoma Screening for more information.)

This phenomenon has been well described in infants, especially in those with the 4S pattern of metastatic spread.[68] (Refer to the Stage Information section of this summary for more information.) In a German clinical trial, spontaneous regression and/or lack of progression occurred in nearly half of 93 asymptomatic infants aged 12 months or younger with stage 1, 2, or 3 tumors without MYCN amplification; all were observed after partial or no resection.[69] Regression generally occurs only in tumors with a near triploid number of chromosomes, no MYCN amplification, and no loss of chromosome 1p. Additional features associated with spontaneous regression [70,71] include the lack of telomerase expression,[72,73] the expression of Ha-ras,[74] and the expression of the neurotrophin receptor TrkA, a nerve growth factor receptor.

Studies have suggested that selected infants who appear to have asymptomatic, small, low-stage adrenal neuroblastoma detected by screening or during prenatal or incidental ultrasound examination, often have tumors that spontaneously regress and may be observed safely without surgical intervention or tissue diagnosis.[75-77]

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